Alzheimer's disease is the most common form of senile dementia and the fourth highest cause of disability and death in the elderly. It is characterized by the presence of three main brain hallmarks viz. diffuse neuronal loss with a particular involvement of the cholinergic system, extracellular protein deposits (amyloid plaques) and intracellular protein deposits (neurofibrillary tangles, NFTs). All current therapies are based on the cholinergic hypothesis and demonstrate only symptomatic treatment. Progression of the disease is not slowed or halted, with symptoms continuing to deteriorate over time. The amyloid hypothesis proposes that Alzheimer's disease is caused by an imbalance between Aβ production and clearance, resulting in increased amounts of Aβ in various forms such as monomers, oligomers, insoluble fibrils and plaques in the CNS. The rate of Aβ production is same as that in healthy volunteers; whereas rate of clearance is impaired by 25-30%. High levels of Aβ then initiate cascade of events culminating in neuronal damage and death manifesting as progressive dementia of the Alzheimer's disease type. Evidence shows that insufficient clearance of the Aβ protein is a prime cause in over 95% of Alzheimer's disease patients (Mawuenyega, K. G. et al. Science 2010, 330, 1774). Further, it is known that Aβ efflux is mediated by p-glycoprotein efflux pump. The p-glycoprotein deficiency at the blood brain barrier increases Aβ deposition in an Alzheimer's disease (Cirrito, J. R. et al., J. Clin. Invest. 2005, 115, 3285). P-glycoprotein (Pgp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the blood brain barrier. There is a direct link between Pgp and Aβ metabolism in vivo. The Pgp activity at the blood brain barrier could affect risk for developing Alzheimer's disease as well as provide a novel diagnostic and therapeutic target (Lam, F. C. et al., J. Neurochem. 2001, 76, 1121). Thus, it is evident that drugs that have ability to increase levels of Pgp should increase amyloid-β clearance. The present invention reports identification of new Pgp inducers, showing efficacy at low nanomolar concentrations, and thus have potential to emerge as a treatment for Alzheimer's disease.
SR-12813 [tetra-ethyl 2-(3,5-di-tert-butyl-4-hydroxy-phenyl)ethenyl-1,1-bisphosphonate, 1a] is a bisphosphonate ester possessing in-vitro as well as in-vivo cholesterol lowering activity. It lowers cholesterol by increasing the degradation of the HMG-Co A (3-hydroxy-3-methylglutaryl-coenzyme A) reductase enzyme (Berkhout, T. A et al., J. Biol. Chem. 1996, 271, 14376-14382) which is a key component of the fatty acid and cholesterol biosynthesis pathway. In HepG2 (hepatocellular carcinoma) cells, SR-12813 reduces the activity of the HMG-Co A reductase with IC50 value of 0.85 μM. In-vivo, it causes overexpression of LDL (low-density lipoprotein) receptor mediated LDL uptake which explains its anti-hypocholesterolemic effects (Watkins, R. E. et al., Science 2001, 292, 2329-2333).
SR12813 (1a) is a very potent and efficacious activator of both human and rabbit PXR, with EC50 values of approximately 200 nM and 700 nM, respectively (Jones, S. A. et al., Mol. Endocrinol. 2000, 14, 27-39). SR12813 has been reported to increase CYP3A4 protein levels in rat hepatocytes. In the absence of nuclear receptor regulatory domain SRC-1 (steroid receptor co-activator-1), SR12813 binds at multiple orientations to PXR, whereas in the presence of SRC1, the binding occurs in a fixed orientation. By contrast, SR12813 is very weak activator of rat and mouse PXR (Watkins, R. E. et al., J. Mol. Biol. 2003, 331, 815-828). Apart from this, SR12813 has also been reported in treatment of bone diseases (WO2002011704, WO0211704A2), activation of orphan nuclear receptors (WO9948915A1), SXR modulation (WO0172837A2), as antineoplastic agent (WO9704785A1), reduction of hair growth (US2006269496A1), for migraine headaches (WO2011085293A1, CA2823974), induction of CYP3A4 & CYP2C8 (US20020022599), treatment of metabolic disorders caused by the sterol 17-hydroxylase (CYP27) deficiency like cerebrotendinous xanthomatosis, tendon xanthomos (US-200400190027), and as chemopreventive agent in fibrosis caused by radiation treatment (WO2009026428) showed promising Pgp induction activity in LS-180 cells.

There arises a need to identify new Pgp inducers, showing efficacy at low nanomolar concentrations, and thus have potential to emerge as a treatment for Alzheimer's disease. Therefore, the present invention provides stable compounds which show Pgp induction at low nanomolar concentrations, showed optimal water solubility.